tbuckley/cabot-search huggingface dataset:
Impaired TIGIT expression on B cells drives circulating follicular helper T cell expansion in multiple sclerosis
Authors: Hiromitsu Asashima, Pierre-Paul Axisa, Thi Hong Giang Pham, Erin E. Longbrake, William E. Ruff, Nikhil Lele, Inessa Cohen, Khadir Raddassi, Tomokazu S. Sumida, David A. Hafler
Journal: Journal of Clinical Investigation (2022)

B cell depletion in patients with relapsing-remitting multiple sclerosis (RRMS) markedly prevents new MRI-detected lesions and disease activity, suggesting the hypothesis that altered B cell function leads to the activation of T cells driving disease pathogenesis. Here, we performed comprehensive analyses of CD40 ligand- (CD40L-) and IL-21-stimulated memory B cells from patients with MS and healthy age-matched controls, modeling the help of follicular helper T cells (Tfh cells), and found a differential gene expression signature in multiple B cell pathways. Most striking was the impaired TIGIT expression on MS-derived B cells mediated by dysregulation of the transcription factor TCF4. Activated circulating Tfh cells (cTfh cells) expressed CD155, the ligand of TIGIT, and TIGIT on B cells revealed their capacity to suppress the proliferation of IL-17-producing cTfh cells via the TIGIT/CD155 axis. Finally, CCR6+ cTfh cells were significantly increased in patients with MS, and their frequency was inversely correlated with that of TIGIT+ B cells. Together, these data suggest that the dysregulation of negative feedback loops between TIGIT+ memory B cells and cTfh cells in MS drives the activated immune system in this disease.
Revolutionizing cardiovascular medicine: targeted therapies for the cardiac conduction system
Authors: Daniel J. Garry, Demetris Yannopoulos, Tamas Alexy
Journal: Journal of Clinical Investigation (2022)

Arrhythmogenic cardiovascular disorders are associated with considerable morbidity and mortality. Whether cardiac conduction disease is caused by genetic defects, procedural perturbations, valvular disease, ischemia, aging, or heart failure, new therapies are warranted. In this issue of the JCI, Goodyer et al. used state-of-the-art technologies to image the cardiac conduction system (CCS) in real time and to deliver targeted therapies to the CCS and its subcomponents. These findings advance the ability to image and treat specific lineages within the adult heart with the potential for broader applications in the treatment of cardiovascular diseases.
Type 1 diabetes: what is the role of autoimmunity in β cell death?
Authors: Marc Y. Donath
Journal: Journal of Clinical Investigation (2022)

The current dogma of type 1 diabetes pathogenesis asserts that an autoimmune attack leads to the destruction of pancreatic β cells, with subsequent hyperglycemia. This dogma is based on islet autoantibodies emerging prior to the onset of type 1 diabetes. In this issue of the JCI, Warncke et al. report on their investigation of the development of hyperglycemia below the diabetes threshold as an early proxy of β cell demise. Surprisingly, they found that an elevation in blood glucose preceded the appearance of autoimmunity. This observation calls into question the importance of autoimmunity as the primary cause of β cell destruction and has implications for prevention and treatment in diabetes.
SZT2 maintains hematopoietic stem cell homeostasis via nutrient-mediated mTORC1 regulation
Authors: Na Yin, Gang Jin, Yuying Ma, Hanfei Zhao, Guangyue Zhang, Ming O. Li, Min Peng
Journal: Journal of Clinical Investigation (2022)

The mTORC1 pathway coordinates nutrient and growth factor signals to maintain organismal homeostasis. Whether nutrient signaling to mTORC1 regulates stem cell function remains unknown. Here, we show that SZT2 - a protein required for mTORC1 downregulation upon nutrient deprivation - is critical for hematopoietic stem cell (HSC) homeostasis. Ablation of SZT2 in HSCs decreased the reserve and impaired the repopulating capacity of HSCs. Furthermore, ablation of both SZT2 and TSC1 - 2 repressors of mTORC1 on the nutrient and growth factor arms, respectively - led to rapid HSC depletion, pancytopenia, and premature death of the mice. Mechanistically, loss of either SZT2 or TSC1 in HSCs led to only mild elevation of mTORC1 activity and reactive oxygen species (ROS) production. Loss of both SZT2 and TSC1, on the other hand, simultaneously produced a dramatic synergistic effect, with an approximately 10-fold increase of mTORC1 activity and approximately 100-fold increase of ROS production, which rapidly depleted HSCs. These data demonstrate a critical role of nutrient mTORC1 signaling in HSC homeostasis and uncover a strong synergistic effect between nutrient- and growth factor-mediated mTORC1 regulation in stem cells.
The curious case of tryptophan in pregnancy
Authors: Philip A. Marsden
Journal: Journal of Clinical Investigation (2022)

For patients and caregivers to be fully informed about how living organ donation or prior kidney injury affects future health, we need to better understand the role of kidney reserve in physiological adaptation, especially during pregnancy. Importantly, epidemiological studies reason that live kidney donors are at increased risk for developing preeclampsia, a hypertensive disorder of pregnancy with serious implications for maternal and fetal health. Despite the import of this finding, the mechanistic basis for this increased risk is not understood. In this issue of the JCI, Dupont, Berg, and co-authors provide strong evidence that impaired placental perfusion, placental ischemia, increased soluble fms-like tyrosine kinase 1 (sFLT1), and a maternal preeclampsia-like phenotype are associated with an inability to upregulate the l-tryptophan-derived l-kynurenine pathway during pregnancy in mice with blunted renal reserve. These surprising revelations underscore the curious quiddity of l-tryptophan.
IL-1β–dependent extravasation of preexisting lung-restricted autoantibodies during lung transplantation activates complement and mediates primary graft dysfunction
Authors: Wenbin Yang, Emily Jeong Cerier, Félix L. Núñez-Santana, Qiang Wu, Yuanqing Yan, Chitaru Kurihara, Xianpeng Liu, Anjana Yeldandi, Nigar Khurram, Diego Avella-Patino, Haiying Sun, G.R. Scott Budinger, Daniel Kreisel, Thalachallour Mohanakumar, Emilia Lecuona, Ankit Bharat
Journal: Journal of Clinical Investigation (2022)

Preexisting lung-restricted autoantibodies (LRAs) are associated with a higher incidence of primary graft dysfunction (PGD), although it remains unclear whether LRAs can drive its pathogenesis. In syngeneic murine left lung transplant recipients, preexisting LRAs worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor nonclassical monocytes and host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecules were necessary for lung injury, which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin in recipient mice failed to rescue lung function. LRA-mediated injury was localized to the transplanted lung and dependent on IL-1β–mediated permeabilization of pulmonary vascular endothelium, which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL-1R in the donor lungs prevented LRA-induced graft injury. In humans, preexisting LRAs were an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that preexisting LRAs can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.
Elevations in blood glucose before and after the appearance of islet autoantibodies in children
Authors: Katharina Warncke, Andreas Weiss, Peter Achenbach, Thekla von dem Berge, Reinhard Berner, Kristina Casteels, Lidia Groele, Konstantinos Hatzikotoulas, Angela Hommel, Olga Kordonouri, Helena Elding Larsson, Markus Lundgren, Benjamin A. Marcus, Matthew D. Snape, Agnieszka Szypowska, John A. Todd, Ezio Bonifacio, Anette-G. Ziegler
Journal: Journal of Clinical Investigation (2022)

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.
PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [177Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial
Authors: James P Buteau, Andrew J Martin, Louise Emmett, Amir Iravani, Shahneen Sandhu, Anthony M Joshua, Roslyn J Francis, Alison Y Zhang, Andrew M Scott, Sze-Ting Lee, Arun A Azad, Margaret M McJannett, Martin R Stockler, Scott G Williams, Ian D Davis, Michael S Hofman, Tim Akhurst, Ramin Alipour, Arun A Azad, Patricia Banks, Alexis Beaulieu, James P Buteau, Wei Chua, Ian D Davis, Nattakorn Dhiantravan, Louise Emmett, Kate Ford, Michael S Hofman, Roslyn J Francis, Craig Gedye, Jeffrey C Goh, Alex Guminski, Anis Hamid, Mohammad B Haskali, Rodney J Hicks, Edward Hsiao, Amir Iravani, Anthony M Joshua, Ian D Kirkwood, Grace Kong, Edmond M Kwan, Ailsa Langford, Nicola Lawrence, Sze-Ting Lee, Jeremy Lewin, Peter Lin, Andrew J Martin, William McDonald, Margaret M McJannett, Kate Moodie, Declan G Murphy, Siobhan Ng, David A Pattison, Izabella Pokorski, Shakher Ramdave, Aravind S Ravi Kumar, Andrew D Redfern, Natalie K Rutherford, Javad Saghebi, Shahneen Sandhu, Andrew M Scott, Lavinia Spain, Martin R Stockler, Shalini Subramaniam, Thean Hsiang Tan, Sue Ping Thang, Ben Tran, Roslyn Wallace, Andrew Weickhardt, Scott G Williams, Sonia Yip, Alison Y Zhang
Journal: The Lancet Oncology (2022)
Disrupting biofilm and eradicating bacteria by Ag-Fe3O4@MoS2 MNPs nanocomposite carrying enzyme and antibiotics
Authors: Mirza Muhammad Faran Ashraf Baig, Arshia Fatima, Xiuli Gao, Awais Farid, Muhammad Ajmal Khan, Abdul Wasy Zia, Hongkai Wu
Journal: Journal of Controlled Release (2022)
Use of Straighteners and Other Hair Products and Incident Uterine Cancer
Authors: Che-Jung Chang, Katie M O’Brien, Alexander P Keil, Symielle A Gaston, Chandra L Jackson, Dale P Sandler, Alexandra J White
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Hair products may contain hazardous chemicals with endocrine-disrupting and carcinogenic properties. Previous studies have found hair product use to be associated with a higher risk of hormone-sensitive cancers including breast and ovarian cancer; however, to our knowledge, no previous study has investigated the relationship with uterine cancer. Methods We examined associations between hair product use and incident uterine cancer among 33 947 Sister Study participants aged 35-74 years who had a uterus at enrollment (2003-2009). In baseline questionnaires, participants in this large, racially and ethnically diverse prospective cohort self-reported their use of hair products in the prior 12 months, including hair dyes; straighteners, relaxers, or pressing products; and permanents or body waves. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations between hair product use and uterine cancer using Cox proportional hazard models. All statistical tests were 2-sided. Results Over an average of 10.9 years of follow-up, 378 uterine cancer cases were identified. Ever vs never use of straightening products in the previous 12 months was associated with higher incident uterine cancer rates (HR = 1.80, 95% CI = 1.12 to 2.88). The association was stronger when comparing frequent use (&amp;gt;4 times in the past 12 months) vs never use (HR = 2.55, 95% CI = 1.46 to 4.45; Ptrend = .002). Use of other hair products, including dyes and permanents or body waves, was not associated with incident uterine cancer. Conclusion These findings are the first epidemiologic evidence of association between use of straightening products and uterine cancer. More research is warranted to replicate our findings in other settings and to identify specific chemicals driving this observed association.
The Enhancing Oncology Model: Leveraging improvement science to increase health equity in value-based care
Authors: Tej A Patel, Bhav Jain, Ravi B Parikh
Journal: JNCI Journal of the National Cancer Institute (2022)

The Oncology Care Model (OCM), launched in 2016 by the Centers for Medicare and Medicaid Services, was the first demonstration of value-based payment in oncology. Although the OCM delivered mixed results in terms of quality of care and total episode costs, the model had no statistically significant impact on remediating racial, ethnic, and socioeconomic disparities among beneficiaries. These deficits have been prominent in other aspects of US healthcare, and as a result, the Institute for Healthcare Improvement has advocated for stakeholders to leverage improvement science, an applied science that focuses on implementing rapid cycles for change, to identify and overcome barriers to health equity. With the announcement of the new Enhancing Oncology Model, a continuation of the OCM's efforts in introducing value to cancer care for episodes surrounding chemotherapy administration, both policymakers and providers must apply tenets of improvement science and make eliminating disparities in alternative payment models a forefront objective. In this commentary, we discuss previous inequities in alternative payment models, the role that improvement science plays in addressing health-care disparities, and steps that stakeholders can take to maximize equitable outcomes in the Enhancing Oncology Model.
Intestine-derived α-synuclein initiates and aggravates pathogenesis of Parkinson’s disease in Drosophila
Authors: Wei Liu, Kah-Leong Lim, Eng-King Tan
Journal: Translational Neurodegeneration (2022)

Abstract Background Aberrant aggregation of α-synuclein (α-syn) is a key pathological feature of Parkinson’s disease (PD), but the precise role of intestinal α-syn in the progression of PD is unclear. In a number of genetic Drosophila models of PD, α-syn was frequently ectopically expressed in the neural system to investigate the pathobiology. Method We investigated the potential role of intestinal α-syn in PD pathogenesis using a Drosophila model. Human α-syn was overexpressed in Drosophila guts, and life span, survival, immunofluorescence and climbing were evaluated. Immunofluorescence, Western blotting and reactive oxygen species (ROS) staining were performed to assess the effects of intestinal α-syn on intestinal dysplasia. High‐throughput RNA and 16S rRNA gene sequencing, quantitative RT‐PCR, immunofluorescence, and ROS staining were performed to determine the underlying molecular mechanism. Results We found that the intestinal α-syn alone recapitulated many phenotypic and pathological features of PD, including impaired life span, loss of dopaminergic neurons, and progressive motor defects. The intestine-derived α-syn disrupted intestinal homeostasis and accelerated the onset of intestinal ageing. Moreover, intestinal expression of α-syn induced dysbiosis, while microbiome depletion was efficient to restore intestinal homeostasis and ameliorate the progression of PD. Intestinal α-syn triggered ROS, and eventually led to the activation of the dual oxidase (DUOX)–ROS–Jun N-terminal Kinase (JNK) pathway. In addition, α-syn from both the gut and the brain synergized to accelerate the progression of PD. Conclusions The intestinal expression of α-syn recapitulates many phenotypic and pathologic features of PD, and induces dysbiosis that aggravates the pathology through the DUOX–ROS–JNK pathway in Drosophila . Our findings provide new insights into the role of intestinal α-syn in PD pathophysiology.
Rapid emergence of ceftazidime-avibactam resistance among carbapenem-resistant Enterobacterales in a tertiary-care hospital in Taiwan
Authors: Jia-Arng Lee, Shin-Hei Du, Tai-fen Lee, Yu-Shan Huang, Chun-Hsing Liao, Yu-Tsung Huang, Po-Ren Hsueh
Journal: Journal of Infection (2022)
Revisiting Antiangiogenic Multikinase Inhibitors in the Era of Immune Checkpoint Blockade: The Case of Sorafenib
Authors: Dan G. Duda, Rakesh K. Jain
Journal: Cancer Research (2022)

Abstract The successful development of multikinase inhibitors over the last two decades has revolutionized the management of many malignant cancers. Agents such as the antiangiogenic kinase inhibitor sorafenib have certain advantages such as a broad spectrum of activity against cancer cells, vascular endothelial cells, and pericytes, and are the mainstay of treatment in diseases such as advanced renal or liver cancer. The more recent emergence of immunotherapy—using immune checkpoint blockade—in some of the same diseases has raised important questions about the treatment interaction with antiangiogenic drugs, seven such combinations have been approved for lung, liver, kidney, and endometrial cancers, and multiple combination therapies are being aggressively pursued in the clinic. Thus, revealing mechanisms of action of antiangiogenic kinase inhibitors in combination with immune checkpoint blockade is critical to improving the treatment outcome further. This Landmark commentary on sorafenib in cancer therapy highlights these important questions. See related article by Wilhelm et al., Cancer Res 2004;64:7099–109.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

Intuiting the Tumor MicroenvironmentMultiple computational approaches have been developed that attempt to infer the composition of tissue samples analyzed by bulk RNA sequencing, however, these may not effectively identify rare subsets of cells.Zaitsev and colleagues recently reported on Kassandra, a machine learning tool trained on bulk RNA sequencing from purified cell populations, with a particular focus on immune and stromal cell subtypes.Using computational recombination of sequence data from purified cells, the authors simulated the varying mixtures of cells found across different tumors.The trained algorithm was then tested via comparison against orthogonal single-cell approaches, including mass cytometry, histological imaging, and single-cell sequencing.Kassandra outperformed prior approaches, identifying populations as low as 0.5% to 1% of total cells, including B-and T-cell subtypes that had highly similar transcriptional signatures.Expert Commentary: This approach improves over prior cell-type deconvolution techniques, providing a tool that potentially can be used to study fresh or archival samples where complementary single-cell approaches are not readily feasible.
A Unique FOXA1-Associated Chromatin State Dictates Therapeutic Resistance in Lobular Breast Cancer
Authors: Ryan Blawski, Eneda Toska
Journal: Cancer Research (2022)

Abstract Invasive lobular carcinomas (ILC) are the second most common histologic subtype of breast cancer, accounting for up to 15% of cases. ILC is estrogen receptor (ER) positive, yet its biology is distinct from invasive ductal carcinomas (IDC), and retrospective analyses have indicated a poorer outcome with endocrine therapy. In this issue of Cancer Research, Nardone and colleagues investigated the mechanisms of this differential therapy response in ILC, which cannot be solely explained by the genetic profile of these tumors. The authors conducted a thorough examination of the epigenome of ILC compared with IDC in clinical and preclinical models and revealed an alternative chromatin accessibility state in ILC driven by the pioneer factor FOXA1. FOXA1 regulates its own expression in a feed-forward mechanism by binding to an ILC-unique FOXA1 enhancer site. This results in a FOXA1-ER axis that promotes the transcription of genes associated with tumor progression and tamoxifen resistance. Targeting the FOXA1 enhancer region blocks this transcriptional program and inhibits ILC proliferation. These results shed light on a new epigenetic mechanism driving ILC tumor progression and treatment resistance, which may have profound therapeutic implications. See related article by Nardone et al., p. 3673
Platelet <scp>LGALS3BP</scp> as a Mediator of Myeloid Inflammation in Systemic Lupus Erythematosus
Authors: Hanane El Bannoudi, MacIntosh Cornwell, Elliot Luttrell‐Williams, Alexis Engel, Christina Rolling, Tessa J. Barrett, Peter Izmirly, H. Michael Belmont, Kelly Ruggles, Robert Clancy, Jill Buyon, Jeffrey S. Berger
Journal: Arthritis & Rheumatology (2022)

Objective Platelets are mediators of inflammation with immune effector cell properties and have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). This study investigated the role of platelet‐associated lectin, galactoside‐binding, soluble 3 binding protein (LGALS3BP) as a mediator of inflammation in SLE and as a potential biomarker associated with clinical phenotypes. Methods We performed RNA sequencing on platelets from patients with SLE (n = 54) and on platelets from age‐, sex‐, and race/ethnicity‐matched healthy controls (n = 18) and measured LGALS3BP levels in platelet releasate and in circulating serum. We investigated the association between LGALS3BP levels and the prevalence, disease severity, and clinical phenotypes of SLE and studied platelet‐mediated effects on myeloid inflammation. Results Platelets from patients with SLE exhibited increased expression of LGALS3BP (fold change 4.0, adjusted P = 6.02 × 10 −11 ). Platelet‐released LGALS3BP levels were highly correlated with circulating LGALS3BP (R = 0.69, P &lt; 0.0001), and circulating LGALS3BP levels were correlated with the severity of disease according to the SLE Disease Activity Index (r = 0.32, P = 0.0006). Specifically, circulating LGALS3BP levels were higher in SLE patients with lupus nephritis than in patients with inactive disease (4.0 μg/ml versus 2.3 μg/ml; P &lt; 0.001). Interferon‐α induced LGALS3BP transcription and translation in a megakaryoblastic cell line (MEG‐01) in a dose‐dependent manner. Recombinant LGALS3BP and platelet releasates from SLE patients enhanced proinflammatory cytokine production by macrophages. Conclusions Our results support that platelets act as potent effector cells that contribute to the pathogenesis of SLE by secreting proinflammatory LGALS3BP, which also represents a novel biomarker of SLE clinical activity.